Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia
Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia
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DOI：
10.1371/journal.pone.0088511
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发表时间：
2014-02-10
期刊：
影响因子：
3.7
通讯作者：
Su, Hua
中科院分区：
文献类型：
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作者：
Choi, Eun-Jung;Chen, Wanqiu;Su, Hua
内皮糖蛋白（ENG）是1型遗传性出血性毛细血管扩张症（HHT 1）的致病基因。HHT 1患者的脑动静脉畸形（AVM）患病率高于一般人群和其他HHT亚型患者。HHT 1患者脑AVM的发病机制目前尚不清楚，也没有特定的药物治疗可用于治疗患者。适当的动物模型对于确定脑AVM发展的潜在机制和测试新疗法至关重要。然而，由于在Eng（2fl/2fl）小鼠中删除Eng-floxed序列的困难，创建HHT 1脑AVM模型一直是相当具有挑战性的。为了建立HHT 1脑AVM小鼠模型，我们使用几种Cre转基因小鼠系来删除Eng（2fl/2fl）小鼠中不同细胞类型中的Eng：R26 CreER（他莫昔芬处理后的所有细胞类型）、SM 22 a-Cre（平滑肌和内皮细胞）和LysM-Cre（溶菌酶M阳性巨噬细胞）。将表达血管内皮生长因子的腺相关病毒载体（AAV-VEGF）注射到脑中以诱导局灶性血管生成。我们发现SM 22与Cre介导的Eng缺失成比例，在胚胎中导致出生后大脑、脊髓和肠道中的AVM。使用R26 CreER加局部VEGF刺激在成年小鼠中诱导Eng缺失诱导脑AVM表型。在两种模型中，在脑AVM病变中检测到Eng-null内皮细胞，并与野生型内皮细胞形成嵌合体。然而，胚胎中LysM-Cre介导的Eng缺失即使在VEGF刺激后也不会导致出生后脑中的AVM。在本研究中，我们报告了两种新型HHT 1脑AVM模型，它们模拟了人脑AVM的许多表型，因此可用于研究脑AVM发病机制和测试新疗法。此外，我们的数据表明，巨噬细胞Eng缺失是不够的，内皮Eng纯合缺失是HHT 1脑AVM发展所必需的。
Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl) mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl) mice: R26CreER (all cell types after tamoxifen treatment), SM22a-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adenoassociated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22 proportional to-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.